1. Field of the Invention
The present invention relates to the oral delivery of .beta.-lactam antibiotics which by this route are poorly absorbed and more especially to the enhancement of this delivery by formulations which contain a hydroxyaryl or hydroxyaralkyl acid or salt, amide or ester thereof.
As employed in this application, the term ".beta.-lactam antibiotics" refers to those antibiotics which contain the .beta.-lactam moiety and include the penicillins, cephalosporins and related chemical species.
2. Description of the Prior Art
It is well known to this art that the .beta.-lactam antibiotics which have the common structural feature, a four-member lactam ring, have been described as the most important class of therapeutic agents to combat gram-positive and gram-negative infections. Inspite of their great popularity, it is also well known that a number of the .beta.-lactam antibiotics such as the penicillins, penicillin G, methacillin and carbenicillin, and the cephalosporins, cefaxolin, cephapirin, cephaloridine, cephalothin, cephapirin, cephanone, cefamandole, cefaporole, cefoxitin, cephacetrile, cefmetazole, cefuroxime, cefotaxime, T-1551, the oxacephalosporin, S-6059, ampicillin and amoxicillin show poor oral activity.
The penicillins, which were introduced a number of years ago, suffer from two major disadvantages: poor activity against resistant organisms and lack of oral activity which is due to its inherent instability to gastric acid. The acid instability was partially overcome by the discovery of more acid stable penicillins such as penicillin V, which permit the penicillin to be adsorbed with less degradation and hence produce higher blood levels of the active therapeutic agent. However, in spite of these chemical modifications to produce acid stable, orally effective penicillins, many of the penicillins in clinical use, such as penicillin G, methacillin, carbenicillin and ticarcillin, cannot be administered by the oral route. Even the newer esters of carbenicillin, carfecillin and carindacillin are only 40% absorbed and give low blood levels of carbenicillin.
The second major problem with penicillin antibiotics is their lack of activity against resistant strains of bacteria which produce the degrading enzyme, penicillinase. The earlier semisynthetic penicillins, such as methicillin, oxacillin, cloxacillin, dicloxacillin, flucloxacillin and nafcillin, were developed to overcome this problem. This class of penicillins were resistant to the penicillinase enzyme and were active against those resistant organisms which produce the enzyme. However, these compounds were less active than their parents and in particular showed poor activity against the important gram-negative organisms.
The second class of .beta.-lactam antibiotics, the cephalosporins, were developed because they, unlike the penicillins, were very active against both the penicillinase producing gram-positive bacteria and the gram-negative bacteria. However, lack of oral activity, an almost universal characteristic of the cephalosporins, is shared by the parent molecule, cephalosporin C, and most of the newer semisynthetic analogues. This lack of oral activity was totally unexpected because the cephalosporins, unlike the penicillins, are stable in gastric acid. Since the molecule is excreted unchanged in the feces, it is apparent that the lack of oral activity is due to poor absorption and is probably caused by the polar nature of the cephalsoporin nucleus. Through chemical modification a number of orally effective .beta.-lactam antibiotics were prepared, such as cephalexin, cephradine, cephaloglycin, cefdioxil and cefaclor, which have been shown to be greater than 80% absorbed. Unfortunately, they are much less active in vitro than the clinically injectable cephalosporins. It is clear that this chemical modification has produced an orally active antibiotic whose antibacterial properties are inferior to those of the currently used injectable cephalosporins.
Thus, there exists a clear and present need for a novel method to enhance the oral absorption of the non-orally effecitive .beta.-lactam antibiotics. Said method would permit the oral use of the clinically important .beta.-lactam antibiotics whose use is presently limited to intramuscular and intravenous administration.